Lyophilization Container And Method Of Using Same

ABSTRACT

Provided is a multi-part lyophilization container for lyophilizing a fluid, storing the lyophilizate, reconstituting the lyophilizate, and infusing the reconstituted lyophilizate into a patient, including a method of using same. The container includes a front surface, a back surface, a non-breathable section including a port region, a breathable section including a breathable membrane, and an occlusion zone encompassing a boundary between the non-breathable section and the breathable section. The non-breathable section is configured to accommodate any of a liquid, a solid, a gas or combination thereof. The breathable section is configured to accommodate only a gas. The method includes creating a temporary seal between the non-breathable section of the container and the breathable section, inputting a liquid into the non-breathable section, freezing the liquid, removing the temporary seal to allow vapor transport between the non-breathable section and the breathable section, and adding heat energy the frozen liquid under vacuum.

This application claims priority to each of U.S. Provisional PatentApplication No. 62/569,858, entitled “Lyophilization and StorageContainer for Freeze Dried Blood Products,” filed in the U.S. Patent andTrademark Office on Oct. 9, 2017 and U.S. Provisional Patent ApplicationNo. 62/571,087, entitled “Lyophilization and Storage Container forFreeze Dried Blood Products,” filed in the U.S. Patent and TrademarkOffice on Oct. 11, 2017, each of which are incorporated by referenceherein in their entirety.

The invention was made with government support under grant numberH92222-16-C-0081 awarded by the United States Department of Defense. Thegovernment has certain rights in the invention.

BACKGROUND

The present application describes a device and related method forlyophilizing (freeze-drying) and storing a fluid. The device is acontinually evolving, multi-section lyophilization container thatevolves throughout the stages of filling, lyophilization, storage,reconstitution and infusion. The method is a means by which the deviceis manipulated throughout the lyophilization process. In embodiments ofthe instant application, lyophilization of the fluid occurs in situwithin the multi-section lyophilization container.

Any suitable fluid may be lyophilized and stored using the devices andtechniques described in this disclosure, including human and animalblood and related blood products, such as blood plasma.

The advantages of lyophilization and the relative benefits of storingand transporting lyophilized products have been known for many years.Unfortunately, several technical challenges must be addressed beforelyophilization can enjoy greater adoption in the blood and blood relatedfields. One such challenge is that many methods use glass containerswhich tend to be large and breakable. In this respect, a flexible pouchwould be an improvement. Further, current methods suffer from prolongeddrying times resulting from restricted vapor transmission to thecondenser of the lyophilizer. Another challenge is that currentlyophilization techniques include pathways by which both the blood, andthe technician, may be subject to contamination. A yet furtherchallenge, specific to techniques utilizing a flexible containerincluding a breathable membrane, is a limitation in vapor flow caused bya wetting and fouling (i.e., blocking) of the breathable membranethroughout the lyophilization process which leads to relatively slowlyophilization times. Additionally, current devices include anarrangement of breathable and non-breathable elements which fails toprovide adequate total breathable surface area, resulting inunderperformance.

Because of these and other problems associated with the state of theart, the traditional approach to freezing, storing and transportingfrozen blood and blood products remains the approach most commonlydeployed. Problematically, traditional freezing, storage andtransportation of blood and blood products requires the blood to bemaintained at a temperature that is typically −20° C. or below tomaintain protein integrity. This, in turn, necessitates cold chainmanagement which dramatically increases the costs and logistical hurdlesassociated with traditional methods. For example, cold chain managementrequires the implementation of systems and protocols capable ofeffectively processing orders and providing reliable transportation anddelivery of frozen products that then require thawing prior totransfusion. These requirements can present significant challenges indeveloping regions suffering from lack of resources and lack ofinfrastructure capable of accommodating the complex requirements of thecold chain logistics just described. Often, the result is that patientsin dire need of transfusion in developing nations. Accordingly, despitetheir predominance, traditional methods remain burdened bydisadvantages, particularly in connection with blood requiring storagefor long periods or requiring temperature-controlled transportation overlarge distances.

Consequently, a strong interest remains in lyophilization as analternative to traditional methods for freezing, storing andtransporting blood and blood products. A lyophilized blood product, suchas plasma, may have much smaller mass than a traditional product, has alonger shelf life and does not require extensive cold chain managementor lengthy thawing procedures. Additionally, since a lyophilized bloodproduct can be easily and rapidly reconstituted at its point of use, alyophilized blood product is often preferable in battlefieldenvironments, in emergency response situations and in various clinicalapplications. For these and other reasons, there remains a need toimprove current lyophilization devices and techniques in relation toblood and blood products.

Although specific embodiments of the present application are provided inview of these and other considerations, the specific problems discussedherein should not be interpreted as limiting the applicability of theembodiments of this disclosure in any way.

SUMMARY

This summary is provided to introduce aspects of some embodiments of thepresent application in a simplified form and is not intended to comprisean exhaustive list of all critical or essential elements of the claimedinvention, nor is it intended to limit the scope of the claims.

Embodiments provide for a multi-part lyophilization container. Thecontainer includes a front surface, a back surface, a non-breathablesection including a port region, a breathable section including abreathable membrane, and an occlusion zone encompassing a boundarybridging the non-breathable section and the breathable section. Thenon-breathable section is configured to accommodate any of a liquid, asolid and a gas, whereas the breathable section is configured toaccommodate only a gas.

In another aspect, provided is a method of lyophilizing a fluid in amulti-part container. The method includes creating a temporary sealdividing a non-breathable section of the container and a breathablesection of the container, inputting a liquid into the non-breathablesection of the container, freezing the liquid, opening the temporaryseal to allow vapor flow between the non-breathable section of thecontainer and the breathable section of the container, and adding heatenergy to the frozen liquid under vacuum, wherein the breathable sectionis configured to accommodate only a gas.

Further embodiments of the present application include additionalmethods and devices and systems for lyophilizing fluids. The fluid maybe any suitable liquid, including human or animal plasma.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting and non-exhaustive embodiments are described with referenceto the following figures.

FIGS. 1A and 1B are plan and perspective views of a lyophilizationcontainer according to an embodiment of the present application;

FIGS. 2A and 2B are plan and perspective views of another lyophilizationcontainer according to an embodiment of the present application;

FIG. 3A is a plan view of a non-breathable section of a lyophilizationcontainer according to an embodiment of the present application;

FIG. 3B is an expanded view of the port region of the non-breathablesection of the lyophilization container of FIG. 3A;

FIG. 4 is a plan view of a breathable section of a lyophilizationcontainer according to an embodiment of the present application;

FIG. 5 is a section view of the Hold Open Device (HOD) of the breathablesection of the lyophilization container of FIG. 4;

FIG. 6 is an expanded view of the HOD capture void of the breathablesection of the lyophilization container of FIG. 4;

FIG. 7 is a side section view of an alternative configuration of anocclusion zone according to an embodiment of the present application;

FIG. 8 is a workflow schematic illustrating an intermittent occlusion ofa lyophilization container according to an embodiment of the presentapplication; and

FIG. 9 is workflow schematic illustrating an intermittent occlusion of alyophilization container according to another embodiment of the presentapplication.

DETAILED DESCRIPTION

The principles described in the present application may be furtherunderstood by reference to the following detailed description and theembodiments depicted in the accompanying drawings. Although specificfeatures are shown and described below with respect to particularembodiments, the present application is not limited to the specificfeatures or embodiments provided. Moreover, embodiments below may bedescribed with respect to lyophilizing and storing human or animal bloodor blood components; however, such descriptions are merely illustrative.Those of skill in the art will appreciate that embodiments of thisdisclosure may be used in connection with the lyophilization of anysuitable liquid.

Embodiments of the present application refer to a closed, sterilecontainer, including sterile fluid pathways, for lyophilizing andstoring a fluid, thus obviating the need for a clean room. Moreover,embodiments described in this application may be implemented inconjunction with many conventional, commercially available lyophilizers,such as the EPIC Small Production Lyophilizer by Millrock Technology.Accordingly, the devices and techniques described in this applicationmay be more widely distributed and widely accessible than are existingdevices and techniques. Further advantages of the various enumeratedembodiments are noted throughout this disclosure.

The terms “multi-part container,” “container,” “lyophilizationcontainer,” “multi-part lyophilization container,” and the like, areused interchangeably throughout this disclosure. Similarly, the term“breathable,” with respect to materials and membranes, may be usedinterchangeably with the term “semi-permeable.” The term“non-breathable” may be used interchangeably with the term“non-permeable.”

FIGS. 1A and 1B are plan and perspective views of a lyophilizationcontainer according to an embodiment of the present application.

Referring to FIG. 1A, the lyophilization container 100 includes anon-breathable section 102, including a port region 104; a breathablesection 106, including a breathable membrane 108 and an inner membraneweld 110; an outer perimeter weld 112; and an occlusion zone 114.

As shown in FIGS. 1A and 1B, the lyophilization container 100 isessentially rectangular and is comprised of two principal sections:non-breathable section 102 and breathable section 106, joined inocclusion zone 114. Non-breathable section 102 and breathable section106 are in communication with one another in a native or normal state,and together encapsulate the container cavity. Port region 104 definesan area within non-breathable section 102 that is configured toincorporate one or more fluidic ports. Breathable membrane 108 isincorporated into breathable section 106 by inner membrane weld 110,which is a sterile seal. Outer perimeter weld 112 is also a sterile sealand defines the outer perimeter of the lyophilization container 100,including the port region 104.

The overall length of the lyophilization container 100, denoted as “L,”including both the non-breathable section 102 and the breathable section106, is approximately 50 cm. In embodiments, L may be any dimensionsuitable for placement of the container in a shelf lyophilizer or otherlyophilizer, any dimension required to increase or decrease vapor flowresistance, or any dimension to increase or decrease the thickness ofthe frozen liquid, such as between 30 cm and 70 cm, or more preferablybetween 40 cm and 60 cm. The width of the container, denoted as “W,” isapproximately 15 cm. In embodiments, W may any suitable dimension, suchas between 10 cm and 20 cm, or more preferably, between 13 cm and 17 cm.In the example shown, the length of non-breathable section 106, measuredfrom the midpoint of the occlusion zone, is approximately 28 cm. Inembodiments, the length of non-breathable section 106 may any suitabledimension, such as between 20 cm and 40 cm, or more preferably, between24 cm and 32 cm. The length of breathable section 102, measured from themidpoint of the occlusion zone, is approximately 22 cm. In embodiments,the length of breathable section 106 may any suitable dimension, such asbetween 10 cm and 30 cm, or more preferably, between 18 cm and 26 cm.The exemplary dimensions of 15 cm by 50 cm described above are suited tolyophilize approximately 300 ml of liquid plasma. The lyophilization oflarger or smaller volumes would suggest different preferred dimensions.

Although FIGS. 1A and 1B depict an essentially rectangular container,some embodiments might include geometries that deviate from therectangular shape. For example, the width of only occlusion zone 114might be reduced to less than the width W of the embodiment shown. Suchan adjustment may result in an essentially hourglass shaped container asopposed to a container having a rectangular shape. This type ofadjustment in occlusion zone 114

dimension may better facilitate temporarily sealing of the occlusionzone during the lyophilization process.

The “top” or “front” of the lyophilization container 100 shown isessentially identical to the “bottom” or “back” of the container 100.That is, each of the top and the bottom of the container includesnon-breathable material of the non-breathable section and breathablemembrane of the breathable section. In alternative embodiments, thebreathable membrane comprises a continuous sheet including an isoclinal(i.e., hairpin) fold causing the breathable membrane to bridge a portionof the top or front surface and a portion of the bottom or back surface.In yet another alternative embodiment, the breathable section mightcomprise breathable membrane only on the top of the container or only onthe bottom of the container. In operation, the lyophilization container100 is typically placed on a lyophilizer shelf such that the bottom orback of the container faces the lyophilizer shelf. That is, duringlyophilization, a portion of each of the non-breathable section 102 andthe breathable section 106, including breathable membrane, face thelyophilizer shelf. Non-breathable section 102 should be in sufficientdirect or indirect thermal communication with the lyophilizer shelf tofacilitate conductive and/or radiative heat transfer. In yet furtherembodiments, only the non-breathable section might be in contact withthe shelf and the breathable section might reside off the shelf. Incertain other embodiments, the lyophilization container may be disposedvertically within a lyophilization chamber.

In operation, lyophilization container 100 exchanges fluids via portspositioned in the port region 104 of non-breathable section 102. Fluidexchanges occur only during initial filling of the container with liquidplasma and during the post-lyophilization filling of the container withsterile water for reconstitution and transfusion into a patient. Bothprior to, and after, the sublimation of the frozen fluid and removal ofvapor during lyophilization, non-breathable section 102 and breathablesection 106 are isolated from one another by a creation of an occlusionof the container in the occlusion zone 114 encompassing the transitionbetween the non-breathable section 102 and breathable section 106. Inthis respect, the position of the occlusion within the occlusion zone114 defines the boundary between non-breathable section 102 andbreathable section 106.

Outer perimeter weld 112 defines the outer perimeter of the containerand includes port region 104 of the non-breathable section 102. Outerperimeter weld 112 has an average width of approximately 7 mm. Inembodiments; however, outer perimeter weld 112 may be any suitablewidth, such as between 2 mm and 12 mm, and may further be variable by up3 mm along its length.

Inner membrane weld 110 surrounds the breathable membrane 108 withinbreathable section 106. Inner membrane weld 110 also has average widthof approximately 7 mm; however, in embodiments, inner membrane weld 110may be any suitable width, such as between 2 mm and 12 mm, variable byup 3 mm along its length.

Port region 104 is the portion of the outer perimeter weld 112 ofnon-breathable section 102 configured to incorporate one or more fluidicports capable of forming a sterile fluid pathway between thelyophilization container and any of several other fluid containers. Portregion 104 is also configured to facilitate transfusion to a patient.

In addition to encompassing the boundary between non-breathable section102 and breathable section 106, occlusion zone 114 is adapted tofacilitate the evolution of the container throughout its life cycle.Occlusion of the container 100 in the occlusion zone 114 creates atemporary impermeable or substantially impermeable seal, eliminating thefluid communication between the non-breathable section 102 andbreathable section 106. In operation, an initial occlusion isolatesnon-breathable section 102 from the breathable section 106 prior to theintroduction of fluid via ports in port region 104. Removal or openingof the occlusion upon formation of a frozen ice structure (i.e., afrozen fluid structure to be lyophilized) allows the container to resumeits native state, thus restoring the original container cavity. In therestored state, the container again provides a generous, open pathwayfor vapor flow between the non-breathable section 102 and breathablesection 106. The ability of the container to continually evolve in formand function ensures that no contact occurs between the subject fluidand the breathable section 106 by causing the subject liquid to beisolated and frozen in only the non-breathable section 106 and allowingonly the vapor flow from sublimation and desorption to contact thebreathable section 106. That is, embodiments of the present applicationare configured to create a continuous physical separation between thesubject liquid and the breathable section 106. Accordingly, thenon-breathable section 102 is adapted to accommodate any of a solid, aliquid or a gas, whereas the breathable section 106 is adapted toaccommodate only a gas (i.e., a gas only section).

Occlusion zone 114 is approximately 3 cm in width; however, inembodiments, the occlusion zone may be between 1 cm and 5 cm wide, suchas between 2 cm and 4 cm wide. The nearest edge of the occlusion zone ispreferably positioned within 5 cm of the breathable membrane 108 of thebreathable section 106, but may be positioned between 0.2 cm and 10 cm,such as between 3 cm and 7 cm, from the breathable membrane 108. Theocclusion zone 114 should be sufficiently proximate to the breathablemembrane 108 to ensure the efficient use of container materials and tominimize the distance that vapor must flow to exit the container, yetsufficiently distant from the breathable membrane 108 to allow for thecreation of a permanent seam in non-breathable material between theocclusion and the breathable membrane post lyophilization. The creationof a permanent seam in non-breathable material between the occlusion andthe breathable membrane material post-lyophilization creates a permanentseal, allowing for a permanent separation of container sections and theremoval and disposal of the breathable section 106. Removal of thebreathable section 106 is the final step in the evolution of thecontainer. Removal of the breathable section 106 minimizes the volumeand the mass of the final product, which is desirable for bothtransportation and storage. Additionally, removal of breathable section106 transforms non-breathable section 102 into a more traditionalcontainer suitable for fluid transfusion into a patient.

In embodiments, a visual indication may demarcate the occlusion zone114. For example, the occlusion zone 114 may be indicated by lines, by acolor scheme, or by any other conventional means of visual indication.In embodiments, a choice of material or texture may indicate theposition of the occlusion zone 114. For example, a textured surface mayprovide a visual position indication designed to indicate the positionand boundaries of the occlusion zone 114. In exemplary embodiments,particular materials or textures may also be chosen for one, or both, ofthe inner or outer surfaces of container material in the occlusion zone114 to provide improved sealing characteristics (e.g., smoothmaterials), to impart an improved ability of the materials to pull apartfrom one another, or to pull apart from ice formed during freezing ofthe subject fluid (e.g., textured materials). Notably, materials chosenfor the occlusion zone 114 may be textured or smooth and may be like ordissimilar to one another. Material and design choices for the occlusionzone 114 should consider that an intermittent application and removal ofan occlusion in the occlusion zone 114 must reliably result in theintermittent creation and removal of a temporary impermeable seal.However, it should be noted that in some circumstances, an occlusion maynot be a perfectly impervious or hermetic barrier or seal. That is, incertain situations, minor or insubstantial leakage across an occlusionmay be acceptable.

The creation of an occlusion of the container in the occlusion zone 114may occur by any known means, such as by manual clamping, or by variousautomated or semi-automated means. Exemplary manual clamps may include,but are not limited to, screw clamps or bag clips that are in commonusage. Various automated or semi-automated occlusion means may, forexample, include mechanical compression means incorporated into theshelves of, or the shelf system of, a lyophilizer. In all cases, themeans chosen for creating an occlusion must ensure that fluids inputinto the non-breathable section 102 via port region 104 do not contactbreathable membrane 108 of breathable section 106 at any point.

In embodiments described throughout this disclosure, various additionalfeatures may also be included in non-breathable section 102. Forinstance, a section of relatively clear container material may beincorporated into non-breathable section 102 to allow visual inspectionof the subject fluid before, during or after lyophilization.

In the embodiment shown in FIG. 1, the non-breathable material isethylene-vinyl acetate (EVA). EVA exhibits several advantageousproperties including its relative strength, its relative elasticity andresilience at low temperatures, its relative crack resistance and theease with which it may be manufactured. EVA also exhibits comparativelyfavorable thermal transfer properties. Nonetheless, in embodiments,material choices for non-breathable material are not limited, and mayinclude a variety of non-breathable materials that exhibit preferablecharacteristics, such as thermoplastic elastomers (TPEs). TPEs arerelatively soft and flexible, and exhibit advantages for severalhealthcare applications. For instance, TPEs can be sterilized usingautoclaves, gamma irradiation, or ethylene oxide. Further, TPEs can bedesigned to be biocompatible, to have high purity, and to have lowlevels of extractable and leachable substances. TPEs are also recyclableand are a comparatively favorable material for cryogenic storage.

Linear, low density polyethylene (LLDPE) may also be desirable for useas non-breathable material. LLDPE is preferable to certain othermaterials due to its favorable puncture and impact resistance and to itshigh tensile strength. For instance, as compared to LDPE, LLDPE exhibitssuperior flexibility and resistance to cracking, thus making it moresuitable for certain thin film applications.

Materials selected for non-breathable material must maintain strength atlow temperatures (e.g., −40° C. to −60° C.) as is required forlyophilization. Certain materials exhibiting a low surface energy andsuper-hydrophobicity may further be incorporated into the interiorsurface of the non-breathable section to facilitate an improved releaseof the ice structure from the inner surfaces of the container afterfreezing and before drying.

In embodiments, various additional or alternative plastic films may beincorporated into non-breathable section 102, or to all areas of thecontainer with non-breathable material for a particular purpose orapplication. For example, materials may be implemented for any ofimproved impermeability, improved heat sealing characteristics orimproved mechanical strength.

FIGS. 2A and 2B are plan and perspective views of another lyophilizationcontainer according to an embodiment of the present application.

Referring to FIGS. 2A and 2B, the lyophilization container 200 includesa non-breathable section 202, including a port region 204; a breathablesection 206, including a Hold Open Device (HOD) 208, a breathablemembrane 210; an inner membrane weld 212; an outer perimeter weld 214;and an occlusion zone 216.

As shown in FIGS. 2A and 2B, the lyophilization container 200 isessentially the same as the lyophilization container of FIGS. 1A and 1B,further including a Hold Open Device (HOD) 208. In the embodiment shown,HOD 208 is a semi-rigid, flat-sided elliptical fixture, captured withinthe lyophilization container 200. HOD 208 is in an open mode in itsnative state, disposed circumferentially within the container cavity tofacilitate a pathway for vapor flow between non-breathable section 202and breathable section 206. HOD 208 is positioned entirely within thebreathable section 206, bridging portions of breathable membrane 210 andnon-breathable material. Notably, in embodiments, HOD 208 shape is notlimited, and various alternative HOD 208 designs may be implemented,such as a modified rectangle or other shape capable of facilitatingvapor flow between container sections.

In various embodiments, HOD 208 may be a rigid or a semi-rigid fixturecaptured within, or fastened to the outside of, the breathable sectionof the lyophilization container 200. The exact position of the HOD 208may vary. For example, the HOD 208 may be positioned entirely within thenon-breathable section, or within a region of non-breathable material ofthe breathable section. Alternatively, HOD 208 may extend into portionsof both non-breathable material and breathable material. In yet furtherembodiments, HOD 208 may be positioned and configured to assist in thecreation of the temporary seal between bag sections. Preferably, HOD 208is positioned proximate to the occlusion zone to minimize the distancebetween the HOD 208 and the placement of an occlusion in the occlusionzone 216. In the example shown, the nearest edge of HOD 208 ispositioned approximately 2.5 cm from nearest edge of the occlusion zone216. Nonetheless, HOD 208 placement may be further optimized accordingto a particular container 200 or occlusion zone 216 configuration.

FIG. 3A is a plan view of a non-breathable section of a lyophilizationcontainer according to an embodiment of the present application.

Referring to FIG. 3A, non-breathable section 300 comprises anon-breathable material 302; and an outer perimeter weld 304, includinga port region 306 incorporating fluidic ports 308; and a portion of anocclusion zone 310.

Non-breathable section 300 is comprised of the non-breathable materialdescribed above. The boundaries of non-breathable section 300 includeouter perimeter weld 304, including port region 306, and the midpoint(i.e., estimated position of occlusion) of the occlusion zone. That is,when the container is occluded in the occlusion zone 310, non-breathablesection 300 may be defined as the section of the container on the sideof the occlusion that is non-breathable. When an occlusion is notpresent in the occlusion zone 310, the boundary of the non-breathablesection may be approximated as the midpoint of the occlusion zone, asshown ion FIG. 3A.

FIG. 3B is an expanded view of the port region of the non-breathablesection of the lyophilization container of FIG. 3A.

Referring to FIG. 3B, port region 306 includes three ports 308. Theports 308 define the manner in which the lyophilization containerexchanges fluids with other vessels and containers. The ports 308 mustaccordingly provide secure, sterile connections which eliminate thepotential for breakage, contamination or misconnection, and mustfunction across every phase of use including filling, lyophilization,storage, reconstitution and, in the case of lyophilized plasma,infusion. In embodiments, the configuration and number of ports 308 mayvary depending on a particular application. For instance, embodimentsmay include between 1-5 ports, such as 3 ports. Ports 308 may furtherinclude connections which are either resealable or non-resealable.

Ports 308 shown in FIG. 3B may be adapted to include a variety of ports.For example, ports 308 may include any of a spike port, a docking portand a reconstitution port. A spike port may be included to facilitatereinfusion of a reconstituted blood product into a patient. An exemplaryspike port may be any weldable spike port known in the art which iscompatible for use in lyophilization containers. Examples of suitablematerials for use in spike port include polyvinyl chloride (PVC) andethylene-vinyl acetate (EVA) (e.g., such as is manufactured by Carmo ofDenmark). In other embodiments, a polypropylene (PP) spike port may bedesirable.

A docking port may be included to connect the lyophilization containerwith another fluid container, such as a blood pooling container orpooling container set. A docking port may further be used to introduceair or other gas into the lyophilization container. Air or other gasmay, for example, be introduced to create a vapor space above thesubject liquid or to regulate pH. An exemplary docking port comprisesPVC tubing. In embodiments, however, dock port may include any suitabledocking fixtures or tubing which are known in the art.

A reconstitution port may be included to accept an inflow ofreconstitution fluid into the lyophilization container. An exemplaryreconstitution port 308 may include a male or a female Luer-Lock typeconnection in order to prevent accidental misconnection. One example ofsuch a connection is the Correct Connect® system that is a standardizedconnection system used in apheresis applications. In embodiments,various one-way valves and other means for providing an error proofconnection may also be adapted for use with the reconstitution port 308.Notably, the type of connection used for reconstitution is particularlyimportant. That is, the handling of reconstitution fluids entails thepotential risk of a direct transfusion of the reconstitution fluid intothe patient. Such an event constitutes a serious and immediate healthhazard. For this reason, it is important that the reconstitution portand related connections be highly conspicuous and be incompatible withthe other ports in order to avoid an occurrence of accidentalmisconnection.

FIG. 4 is a plan view of a breathable section of a lyophilizationcontainer according to an embodiment of the present application.

Referring to FIG. 4, breathable section 400 comprises an outer perimeterweld 402, including a Hold Open Device (HOD) capture void 404; a HOD406; a breathable membrane 408; an inner membrane weld 410; and aportion of an occlusion zone 412.

The boundaries of breathable section 400 include outer perimeter weld402 and the midpoint (i.e., estimated position of occlusion) of theocclusion zone 412. That is, when the container is occluded in theocclusion zone 412, breathable section 400 may be defined as the sectionof the container on the side of the occlusion that is breathable. Whenan occlusion is not present in the occlusion zone 412, the boundary ofthe breathable section 400 may be approximated as the midpoint of theocclusion zone, as shown in FIG. 4.

Breathable section 400 comprises breathable membrane 408 embedded withinnon-breathable material. Inner membrane weld 410 is a sterile sealdefining the boundary between the breathable membrane and non-breathablematerial. Outer perimeter weld 402 is a sterile seal defining the outerperimeter of breathable section 400. Outer perimeter weld 402 includesHOD capture voids 404 for capturing HOD 406 within the container.

In certain embodiments, breathable membrane 408 may comprise only onematerial. In other embodiments, breathable membrane 408 may comprise twoor more materials, for example, breathable membrane may comprise amembrane laminate consisting of a breathable membrane and a backingmaterial. In embodiments comprising a laminate, membrane material mayinclude an expanded polytetrafluoroethylene (PTFE). PTFE membranes arepreferable to other membranes for several reasons. For instance,expanded PTFE provides a microstructure that may be preciselycontrolled, which results in the ability to obtain a desired a pore sizedistribution. Further, expanded PTFE is essentially inert, is operableacross a large temperature range and can withstand harsh environments.For at least these reasons, expanded PTFE provides characteristics whichare preferable in comparison to other materials.

An ideal pore size for an expanded PTFE membrane may be between 0.1micron (μm) to 0.5 μm, such as 0.15 μm to 0.45 μm, or 0.2 μm to 0.3 μm.A PTFE membrane having pore sizes in this range exhibits relativelyefficient vapor transmission characteristics while maintaining a sterilebarrier capable of eliminating the ingress of contaminants.

A reinforcing material is designed to bond the breathable section 400 tothe non-breathable section without impairing the functionality of thebreathable membrane 406. The addition of a reinforcing material improvesthe structural integrity of the container. That is, the reinforcingmaterial must bond with the breathable membrane, must bond with thenon-breathable material, and must have a pore size that does not impedevapor transmission across the breathable membrane during lyophilization.Exemplary reinforcing materials are preferably a 50:50polypropylene/polyethylene blend. In embodiments, however, preferableblend ratios may vary and may be between 40:60 and 60:40polypropylene:polyethylene. Polypropylene backing materials areadvantageous, inter alia, for their transition glass temperatures whichare low enough to avoid material degradation during freezing atlyophilization temperatures, such as −40° C.

In embodiments comprising a laminate, various additional or alternativeplastic films may be incorporated into the breathable membrane or to thebacking material to impart desired characteristics, such as favorableheat sealing characteristics, improved permeability, or for overallmechanical strength.

FIG. 5 is a section view of the Hold Open Device (HOD) of the embodimentshown in FIG. 4.

Referring to FIG. 5, HOD 500 is a semi-rigid fixture having anessentially ovular or elliptic shape incorporating pointed ends and flatsides. In the embodiment shown, HOD 500 is captured within thebreathable section proximate to the occlusion zone. In otherembodiments, the HOD 500 may be coupled to the outside of the container.Although generally the HOD 500 is designed to reside in, or on theoutside of, the breathable section of the container, physicallyseparated from the subject liquid throughout the container life cycle,various further embodiments could include HOD 500 in the non-breathablesection.

Incorporation of the elliptic HOD 500 creates a generous open regionabove a thin, uniform structure of ice. Preferably, the thin, uniformice structure has a thickness of from 6 mm to 13 mm, such as 10 mm, tomaximize the efficacy and efficiency of the container. Incorporating theHOD 500 assists in securing a generous vapor pathway between thenon-breathable section and the breathable section and reduces overallvapor pressure in the container during sublimation. HOD 500 may alsocompliment the intermittent creation of occlusions (i.e., temporaryimpermeable or substantially impermeable seals) in the occlusion zone.For example, HOD 500 may impart a tautness to container material whichimproves the reliability or quality of an occlusion. HOD 500 maylikewise assist in the pulling apart of occlusion zone surfacesthroughout the removal of the occlusion, thereby facilitating are-creation of the vapor pathway between container sections. The pullingapart of occlusion zone surfaces can be complicated by the existence ofice formed on, or directly adjacent to, the occlusion as a result of aninadvertent wetting of occlusion zone materials by the subject fluidprior to the freezing step. Such wetting may be caused during thefilling step, or by movement of the container. In this respect, HOD maycompliment other means employed to address problems associated with thepulling apart of occlusion zone surfaces described herein, includingmaterial and related texture choices.

In the embodiment shown, HOD 500 comprises a semi-rigid silicone. Inembodiments, however, several other rigid or semi-rigid materials may beimplemented. For example, PVC or certain other synthetic plasticpolymers may be preferable HOD 500 material. In certain embodiments,semi-rigid materials may be incorporated for their ability to flex inresponse to an occlusion of the occlusion zone. In such embodiments, HODmay compress to some degree upon occlusion of the occlusion zone, andmay rebound toward an original shape upon removal of the occlusion. Suchshape-memory behavior may assist in the maintaining of an open regionabove the subject liquid or ice and in the creation of generous vaporpathway between container sections. This may be especially pronounced inembodiments combining a semi-rigid HOD with other flexible containermaterials.

The external height of HOD 500 shown in FIG. 5 is 2.8 cm; however, inembodiments, external height may vary from 1.5 cm to 4 cm. The internalheight is approximately 2.2 mm; however, in embodiments, the internalheight may vary between 1 cm to 3 cm depending on the exactconfiguration and size of HOD. HOD width is the approximate width of thelyophilization container. HOD 500 depth is approximately 3.5 cm;however, in embodiments HOD depth may be between 0.5 cm and 4 cm. Theoverall size and shape of HOD 500 is not limited, and accordingly mayvary depending on the desired configuration of a particular embodiment.

FIG. 6 is an expanded view of the Hold Open Device (HOD) capture void ofthe breathable section of the lyophilization container of FIG. 4.

Referring to FIG. 6, HOD capture void 600 includes a void space 602,sidewalls 604 and outer perimeter weld 606.

HOD capture void 600 is essentially an indentation or a void withinouter perimeter weld 606 in which the HOD is securely captured. Asshown, the void space 602 has a width which is slightly larger than thewidth of the HOD to accommodate the HOD. Sidewalls 604 are angled atapproximately 45 degrees to the longitudinal axis of the outer perimeterweld. Void space 602 depth is approximately 4 mm.

In embodiments, each of the parameters of the HOD capture void 600 canbe optimized. For instance, HOD void space 602 width may vary accordingto a particular container configuration and may be as much as 20 percentgreater than the width of the HOD. Likewise, HOD void space 602 depthmay vary. For example, HOD void space 602 depth may be between 1 mm and6 mm, such as between 2 mm and 4 mm.

In embodiments, the design of HOD capture void 600 may also vary. Forinstance, sidewall 604 angle may be lesser or greater than 45 degrees.In some cases, the sidewalls 604 may be perpendicular to thelongitudinal axis of the outer perimeter weld 606. In furtherembodiments, sidewall 604 angles may be dissimilar. Likewise, HOD voidspace 602 depth may vary along its length. That is, in embodiments, HODcapture void 600 may be asymmetrical or irregular.

FIG. 7 is a side section view of an alternative configuration of anocclusion zone according to an embodiment of the present application.

Referring to FIG. 7, occlusion zone 700 includes top material 702; dam704; and a liquid 706.

In the embodiment shown in FIG. 7, occlusion zone 700 is incorporatedinto a lyophilization container disposed horizontally on a lyophilizershelf. Top material 702 of occlusion zone 700 comprises non-breathablematerial and is positioned opposite the container cavity from dam 704.Dam 704 is a rigid or semi-rigid container feature capable ofmaintaining a segregation of the liquid 706 input to the non-breathablesection. Dam 704 height measured from the shelf of the lyophilizer canbe any height which exceeds the height of liquid input intonon-breathable section. In this respect, dam 704 prohibits the flow offluid from non-breathable section into breathable section, as shown inFIG. 7.

Dam 704 shown in FIG. 7 comprises a dome shape; however, in embodiments,other dam designs may be desirable. For instance, dam designs includinga flat top, or dam designs configured to cooperate with a particularocclusion device or member (not shown) may be desirable. Similarly,textured materials may be included in dam designs to assist in thecreation of a temporary impermeable seal during occlusion. In yetfurther embodiments, dam features may be incorporated into alyophilization container designed to hang vertically. In embodiments, adam may be included on one or both sides of an occlusion zone tomaintain a segregation of the fluid input into the non-breathablesection.

As noted, embodiments of the lyophilization container(s) describedherein are configured to continually evolve as the lyophilizationprocess moves through its cycle. Exemplary workflows included belowdescribe the manner in which container embodiments may be manipulated toaccomplish container evolution.

FIG. 8 is a workflow schematic illustrating an intermittent occlusion ofa lyophilization container according to an embodiment of the presentapplication.

Referring to FIG. 8, in step 802, an occlusion is created in theocclusion zone. In step 804, a subject fluid (e.g., blood plasma) isintroduced into the non-breathable section through a port in the portregion (e.g., a docking port). In step 806, the liquid in the containeris frozen, creating a thin, uniformly thick structure of ice in thenon-breathable section. In step 808, the occlusion is removed (i.e., thetemporary seal is opened) from the occlusion zone. In step 810, vacuumand heat energy are applied to accomplish sublimation and desorption,causing a phase change in the ice structure from the solid phasedirectly to the vapor phase. Vapor released from the ice structure flowsthrough the container cavity via the unoccluded occlusion zone andescapes through the breathable section, leaving the lyophilized plasmacake (i.e., the ice structure now dehydrated as a result oflyophilization) in the non-breathable section. In step 812, thecontainer is again occluded in the occlusion zone to preventcontamination of the lyophilizate with moisture and oxygen from air. Instep 814, a permanent seam is created in non-breathable material of thebreathable section between the occlusion and the HOD. In step 816, thecontainer is divided at the permanent seam and the breathable section isdiscarded, leaving the lyophilizate in the non-breathable section whichhas now evolved into its final form as a medical infusion bag.

In step 804, the introduction of fluid may be referred to aspre-loading. During preloading, between 250 ml to 500 ml of fluid (e.g.,blood plasma) are input into the non-breathable section of themulti-part lyophilization container. The container is then placedhorizontally on the shelf of a lyophilizer, “front” or “top” side upwardfacing.

In step 810, sublimation and desorption include the application of heatenergy and vacuum. Preferable drying temperatures may range from −20° C.to −40° C., such as −25° C. Owing to the generous vapor pathway betweencontainer sections and the large surface area of breathable membrane inthe breathable section, vapor from the ice structure escapes relativelyfreely from the container. This, in turn, results colder temperaturesduring lyophilization and therefore improved quality of the final dryproduct. In addition, a diminution in sublimation times as compared toconventional lyophilization techniques is realized. Further, embodimentsresult in reduced vapor pressures in, and an increase in mass transferacross, the breathable section, which may result in a sufficient dryingof the ice structure solely during a single drying phase. That is,embodiments may obviate the need for the secondary drying phase oftraditional 2-phase drying methods (i.e., desorption).

In step 812, an occlusion is made in the occlusion zone of thecontainer, creating a temporary seal between the breathable section andthe non-breathable section.

In step 814, a permanent seam is created, isolating the lyophilized cakein the non-breathable section. In the schematic shown, permanent seamstep 814 is a discreet step. That is, an ancillary piece of equipment isused to create the permanent seam or seal. In further examples,permanent seam step 814 may be integrated into occlusion step 812. Insuch embodiments, the occlusion means (e.g., a clamp) may incorporatethe permanent sealing means.

In step 816, the complete removal of the breathable section representsthe final evolution of the container. Removal of the breathable sectioneliminates the potential for moisture and oxygen ingress into the driedproduct, thereby increasing shelf life and plasma stability.Additionally, the reduced size of the final lyophilizate container ismore convenient for each of transportation, storage, reconstitution andinfusion.

In further exemplary workflows, steps may be added to the workflowdescribed in FIG. 8. For example, additional steps may include theintroduction of gas into the lyophilization container to regulate pH orto create a vapor space above the subject fluid or ice structure. In afurther example, an additional step may include backfilling thelyophilization container with an inert gas to regulate containerpressure.

FIG. 9 is workflow schematic illustrating an intermittent occlusion of alyophilization container according to another embodiment of the presentapplication.

Referring to FIG. 9, in step 902, an occlusion is created in theocclusion zone. In step 904, a subject fluid (e.g., blood plasma) isintroduced into the non-breathable section through a port in the portregion (e.g., a docking port). In step 906, air, inert gas, or a pHregulating gas (e.g., CO₂) is introduced into the non-breathable sectionthrough a port in the port region (e.g., a docking port). In step 908,the liquid in the container is frozen, creating a thin, uniformly thickstructure of ice in the non-breathable section. In step 910, theocclusion is removed from the occlusion zone. In step 912, vacuum andheat energy are applied to accomplish sublimation and desorption,causing a phase change in the ice structure from the solid phasedirectly to the vapor phase. Vapor released from the ice structure flowsthrough the container cavity via the unoccluded occlusion zone andescapes through the breathable section, leaving the lyophilized plasmacake in the non-breathable section. In step 914, the container isbackfilled with an inert gas to raise container pressure to partialatmospheric pressure. In step 916, the container is occluded in theocclusion zone to prevent contamination of the lyophilizate. In step918, a permanent seam is created in the non-breathable material of thebreathable section between the occlusion and the HOD. In step 920, thecontainer is divided at the permanent seam and the breathable section isdiscarded, leaving the lyophilized end-product in the non-breathablesection.

FIG. 9 essentially represents a departure from the workflow of FIG. 8only in the addition of steps 906 and 914. In step 906, air (or nitrogenor another inert dry gas), or a pH regulating gas (e.g., CO₂) isintroduced into the lyophilization container. Air can be introduced tocreate a generous physical separation, i.e., a vapor space, between thecontainer material and the preloaded fluid. In exemplary embodiments,the introduction of a vapor space may cause container pressure to reachbetween 0.3 Pound per square inch (Psi) and 1.0 Psi, such as 0.5 Psi(approximately 26 mmHG). Advantageously, the creation of a vapor spacein the container reduces the amount of ice “sticking” to the containermaterial during and after the freezing step. A pH-regulating gas may beintroduced to the lyophilization container to regulate pH. In analternate embodiment, a pH-regulating gas might be introduced duringstep 914 described below.

In step 914, the lyophilization container is backfilled to partialatmospheric pressure with pH regulating gas (e.g., CO₂). In exemplaryembodiments, backfill pressure is 65 Ton (or 65 mmHG) absolute pressure.In embodiments, backfill pressure may range from between 40 mmHG and 90mmHG, such as between 60 mmHG and 70 mmHG. Once at partial atmosphericpressure, the container is occluded, and then permanently sealed insteps 916 and 918, respectively. Occlusion and/or sealing of thecontainer while at a pressure lower than atmospheric pressure causes thecontainer to collapse and reduce its volume when the container isexposed to atmospheric pressure. This process also secures the pHregulating gas in the non-breathable portion and prevents an ingress ofoxygen and moisture into the container. Since the resultant containerhas been occluded and/or sealed at a pressure that is less thanatmospheric pressure, and since final container volume will be in areduced volume condition once the vacuum of the lyophilizer is removed,the final lyophilized product can be stored and transported more easily.Backfilling in this manner is particularly applicable to containerembodiments having flexible materials or components since such adiminution of container volume would not be possible with a rigid,inflexible lyophilization container.

In the workflows described above, the means for creating the occlusionare not limited. For example, occlusion means may be integrated into theflexible container, or may be a reusable piece of equipment external tothe container. In all embodiments, occlusion means must be capable ofcreating a temporary impermeable or substantially impermeable sealbetween the non-breathable section and the breathable section of theevolving multi-part lyophilization container.

The use of a physical barrier (e.g., a clamp) to segregate fluid in thenon-breathable section from the breathable section according toworkflows described above eliminates the potential for fluid contactwith, and fouling of, the pores of breathable material in the breathablesection. Fouling can disrupt the sublimation and desorption aspects oflyophilization, thereby increasing total lyophilization time andreducing the ability to obtain a viable lyophilizate. Accordingly,eliminating the potential for fouling leads to a relative increase invapor flow which, in turn, results in faster freeze drying, a colder icetemperature during primary drying due to an increased sublimativecooling effect and increased retention of proteins and clotting factors.

Moreover, because the lyophilization container is a closed, sterilesystem including sterile fluid pathways, embodiments enablelyophilization to occur in both non-sterile environments and in remotelocations. In this respect, for example, embodiments allowlyophilization to be performed on-site at an ordinary blood center asopposed to a traditional clean room facility. Container embodiments alsoallow flexibility for an operator to freeze and maintain a frozeninventory of plasma in a standard freezer, such as that found in typicalblood bank settings. At a later time, this previously frozen plasma canbe moved to the more specialized lyophilization instrument forsublimation and desorption. Such work flow flexibility results inimproved blood logistics and work flow within the blood bank.

A further advantage of embodiments described herein is the ability toremove the non-breathable section of the lyophilization containerpost-lyophilization. Isolation and removal of the breathable sectionpost-lyophilization results in the creation of a smaller, lighteraseptic container enclosing the final lyophilizate. The resultantcontainer is also both flexible and highly portable. Moreover, since thebreathable section is most vulnerable to moisture and oxygen ingress,its removal can be said to improve the shelf stability of thelyophilizate. The novel use of a temporary occlusion described hereinmakes this advantage possible. That is, in conventional systemsutilizing glass containers, a stopper is mechanically applied to a glasslyophilization container prior to the opening of the lyophilizer inorder to prevent an ingress of moisture and oxygen into the container.In contrast, present embodiments utilize the temporary occlusion toprevent an ingress of moisture and oxygen into the non-breathableportion of the container until a permanent seal can be made betweennon-breathable material portions of the front and back of the container.

The ability of embodiments herein to evolve container configuration, yetto remain a closed, sterile system throughout each phase of containerlifecycle is highly unique and advantageous in the lyophilization space.That is, the present embodiments evolve to achieve significantadvantages over conventional devices and methods during each of filling,lyophilization, transportation, storage, reconstitution and infusion.Accordingly, many of the attributes and advantages described herein arenot possible using conventional devices and approaches, which do notevolve and which require a clean room environment. Importantly in thisregard, the evolving, multi-part containers described herein should befurther considered evolving, multi-function containers insofar as thetype and arrangement of container elements allow the container toaccomplish various functions throughout its lifecycle.

Notwithstanding the various specific embodiments enumerated in thisdisclosure, those skilled in the art will appreciate that a variety ofmodifications and optimizations could be implemented for particularapplications. Additionally, the present application is not limited tothe lyophilization of blood or blood products. That is, the principlesof the present application may be applicable to the lyophilization ofmany fluids. Accordingly, various modifications and changes may be madein the arrangement, operation, and details of the methods and systems ofthe present application which will be apparent to those skilled in theart.

What is claimed is:
 1. A multi-part lyophilization container, thecontainer comprising: a front surface; a back surface; a non-breathablesection including a port region, the non-breathable section configuredto accommodate a liquid, a solid, a gas, or any combination thereof; abreathable section including a breathable membrane, the breathablesection configured to accommodate only a gas; and an occlusion zoneencompassing a boundary bridging the non-breathable section and thebreathable section.
 2. The container of claim 1, wherein the frontsurface and the back surface each comprise a portion of breathablesection including a breathable membrane.
 3. The container of claim 1,wherein the breathable membrane comprises a continuous sheet includingan isoclinal fold allowing the breathable membrane to bridge a portionof the front surface and a portion of the back surface.
 4. The containerof claim 1, wherein the occlusion zone comprises material that is thesame as non-breathable material of the non-breathable section.
 5. Thecontainer of claim 4, wherein the occlusion zone comprises at least twodissimilar materials positioned opposite one another across a spaceformed between the front surface and the back surface of the container.6. The container of claim 1, wherein the occlusion zone comprises avisual indication means.
 7. The multi-part container of claim 1, furthercomprising a Hold Open Device (HOD).
 8. The multi-part container ofclaim 7, wherein the HOD comprises a semi-rigid material.
 9. Themulti-part container of claim 7, wherein the HOD comprises a rigidmaterial.
 10. The multi-part container of claim 9, further comprisingHOD capture voids formed in an outer perimeter weld thereof, withinwhich the HOD is captured.
 11. The multi-part container of claim 7,wherein the HOD is coupled to the outside of the container.
 12. Thecontainer of claim 1, wherein the non-breathable section comprisespolyethylene.
 13. The container of claim 12, wherein the polyethylene isa linear, low density polyethylene.
 14. The container of claim 1,wherein the breathable membrane comprises at least two layers.
 15. Thecontainer of claim 14, wherein the at least two layers of the breathablemembrane comprise a breathable membrane and a reinforcing material. 16.The container of claim 15, wherein the breathable membrane ishydrophobic.
 17. The container of claim 15, wherein the breathablemembrane is an expanded polytetrafluoroethylene (PTFE).
 18. Thecontainer of claim 15, wherein the reinforcing material is apolypropylene/polyethylene blend.
 19. The multi-part container of claim1, wherein the ratio of the surface area of the non-breathable sectionto the surface area of the breathable section is between 5:2 and 5:3.20. A method of lyophilizing a fluid in a multi-part container, themethod comprising: creating a temporary seal dividing a non-breathablesection of the container from a breathable section of the container;inputting a liquid into the non-breathable section of the container;freezing the liquid; opening the temporary seal to allow vapor transferbetween the non-breathable section of the container and the breathablesection of the container; and adding heat energy to the frozen liquidunder vacuum, wherein the breathable section is configured toaccommodate only a gas.
 21. The method of claim 20, further comprisinginputting a gas into the non-breathable section of the container tocreate a vapor space above the inputted liquid.
 22. The method of claim20, further comprising inputting a pH-regulating gas into thenon-breathable section of the container to regulate pH.
 23. The methodof claim 20, further comprising backfilling a lyophilization chamber toa partial atmospheric pressure.
 24. The method of claim 23, wherein thebackfilling of the lyophilization chamber to a partial atmosphericpressure is performed using a pH regulating gas.
 25. The method of claim24, further comprising occluding the container in the occlusion zone.26. The method of claim 25, further comprising forming a permanent seamin the breathable section of the container while the interior of thenon-breathable section is at partial atmospheric pressure.
 27. Themethod of claim 26, further comprising introducing an inert gas to raisechamber pressure to atmospheric pressure.
 28. The method of claim 27,further comprising removing the second section of the flexiblecontainer.